Dissipation assisted Thouless pumping in the Rice-Mele model

We investigate the effect of dissipation from a thermal environment on topological pumping in the periodically-driven Rice-Mele model. We report that dissipation can improve the robustness of pumping quantisation in a regime of finite driving frequencies. Specifically, in this regime, a low-temperature dissipative dynamics can lead to a pumped charge that is much closer to the Thouless quantised value, compared to a coherent evolution. We understand this effect in the Floquet framework: dissipation increases the population of a Floquet band which shows a topological winding, where pumping is essentially quantised. This finding is a step towards understanding a potentially very useful resource to exploit in experiments, where dissipation effects are unavoidable. We consider small couplings with the environment and we use a Bloch-Redfield quantum master equation approach for our numerics: Comparing these results with an exact MPS numerical treatment we find that the quantum master equation works very well also at low temperature, a quite remarkable fact.Comment: 21 pages, 8 figure

Quantum solitons in the XXZ model with staggered external magnetic field

The 1-D 1/2-spin XXZ model with staggered external magnetic field, when restricting to low field, can be mapped into the quantum sine-Gordon model through bosonization: this assures the presence of soliton, antisoliton and breather excitations in it. In particular, the action of the staggered field opens a gap so that these physical objects are stable against energetic fluctuations. In the present work, this model is studied both analytically and numerically. On the one hand, analytical calculations are made to solve exactly the model through Bethe ansatz: the solution for the XX + h staggered model is found first by means of Jordan-Wigner transformation and then through Bethe ansatz; after this stage, efforts are made to extend the latter approach to the XXZ + h staggered model (without finding its exact solution). On the other hand, the energies of the elementary soliton excitations are pinpointed through static DMRG (Density Matrix Renormalization Group) for different values of the parameters in the hamiltonian. Breathers are found to be in the antiferromagnetic region only, while solitons and antisolitons are present both in the ferromagnetic and antiferromagnetic region. Their single-site z-magnetization expectation values are also computed to see how they appear in real space, and time-dependent DMRG is employed to realize quenches on the hamiltonian parameters to monitor their time-evolution. The results obtained reveal the quantum nature of these objects and provide some information about their features. Further studies and a better understanding of their properties could bring to the realization of a two-level state through a soliton-antisoliton pair, in order to implement a qubit

Dissipation effects in driven quantum many-body systems

In this thesis, the effect of dissipation is investigated in driven models of interest for quantum annealing and quantum topological pumping. Dissipation comes from coupling the system to a bosonic bath at thermal equilibrium, using the usual Caldeira-Leggett setting. The first original results presented deal with the dissipative Landau-Zener model, where we revisit the issue of whether dissipation can improve the final ground state probability. We shed light upon the importance of the coupling direction. Then, we move to dissipation effects in the quantum annealing of the Ising chain in transverse field: we study the conditions for the emergence or absence of an optimal annealing velocity, depending on system-bath interaction strength and bath temperature. Finally, we explore dissipation effects in topological pumping in the periodically-driven Rice-Mele model, where we find that a bath at low temperature can improve the pumping performance when adiabaticity is not perfectly fulfilled

Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1.

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses

Targeting cell cycle regulators in hematologic malignancies

© 2015 Aleem and Arceci. Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed

Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias.

PURPOSE: Dasatinib is a dual Src/Abl inhibitor recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We studied growth factor-dependent and growth factor-independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib. RESULTS: Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at approximately 1 x 10(-9) mol/L. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at approximately 1 x 10(-6) mol/L. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI(50) of 5 x 10(-9) mol/L. Primary AML blast cells exhibited a growth inhibition of \u3c1 x\u3e10(-6) mol/L. Cell lines that showed growth inhibition at approximately 1 x 10(-6) mol/L showed a G(1) cell cycle arrest and correlated with accumulation of p21 and p27 protein. The addition of rapamycin or cytotoxic agents enhanced growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. CONCLUSIONS: Although all of the precise targets for dasatinib are not known, this multikinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. The addition of cytotoxic or targeted agents can enhance its effects

ERBB4 confers metastatic capacity in Ewing sarcoma.

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES

Entanglement of formation of mixed many-body quantum states via Tree Tensor Operators

We present a numerical strategy to efficiently estimate bipartite entanglement measures, and in particular the Entanglement of Formation, for many-body quantum systems on a lattice. Our approach exploits the Tree Tensor Operator tensor network ansatz, a positive loopless representation for density matrices which, as we demonstrate, efficiently encodes information on bipartite entanglement, enabling the up-scaling of entanglement estimation. Employing this technique, we observe a finite-size scaling law for the entanglement of formation in 1D critical lattice models at finite temperature for up to 128 spins, extending to mixed states the scaling law for the entanglement entropy

Applicazione dei Teoremi di Stokes e Divergenza alle Equazioni di Maxwell

Nella tesi vengono presentati due degli strumenti più utilizzati nel calcolo integrale in più variabili: il teorema della Divergenza e il teorema di Stokes, entrambi prima in un caso generale, poi nel caso tridimensionale. Prima di arrivare a questi due risultati, introdurremo gli strumenti necessari per l'integrazione su aperti regolari e di calcolo vettoriale esterno. Una volta dimostrati i due teoremi, arriveremo ad enunciare le leggi di Maxwell in forma integrale per trasformarle, applicando i due risultati, in forma differenziale: queste equazioni saranno il nostro punto di partenza per la ricerca di una soluzione per l'equazione d'onda, che definiremo onda elettromagnetica, che governa le interazioni tra campo elettrico e campo magnetico. Utilizzeremo i risultati ottenuti matematicamente per dare al fenomeno un'interpretazione fisica

CELL CYCLE TRANSCRIPTION CONTROL BY UBIQUITIN SIGNALING

The cell cycle is a tightly regulated series of molecular events which dictates proliferation. Both the timely activation of genes through transcription and destruction of proteins through the ubiquitin-proteasome system are integral to normal cell cycles. Dysregulation of these networks often underlie a variety of malignant diseases such as cancer. Forkhead box protein M1 (FOXM1) is an essential cell cycle transcription factor. FOXM1 regulates a transcriptional network that controls the G2/M transition and G1/S transition. Additionally, aberrant upregulation of the FOXM1 transcriptional network is linked to a variety of cancers. The kinases which activate FOXM1 are well explored, but the influence of the ubiquitin-proteasome system on FOXM1 remains unclear. Here, I described the role that two such enzymes, the E3 ubiquitin ligase CUL4-VPRBP and the deubiquitinating enzyme (DUB) USP21, have on the stability and activity of FOXM1 in both normal and dysregulated cell cycles. First, I demonstrate that FOXM1 degradation is enhanced by association with CUL4-VPRBP. Depletion of VPRBP enhances FOXM1 stability and causes mitotic entry defects. Interestingly, overexpression of VPRBP enhances both FOXM1 ubiquitination and transcriptional activity by a process that occurs independent of CUL4. Finally, VPRBP and FOXM1 levels are assessed in high-grade serous ovarian cancer (HGSOC) patient tumors, demonstrating a plausible mechanism for FOXM1 activation. Second, I demonstrate that FOXM1 is protected from degradation through association with the DUB USP21. Knockdown or overexpression of USP21 is able to destabilize or stabilize FOXM1, respectively, through deubiquitination of FOXM1. USP21 is able to influence mitotic entry and proliferation through regulating the FOXM1 transcriptional network. Furthermore, USP21 and FOXM1 are both significantly amplified in basal-like breast cancer with the knockdown of both sensitizing cells to the chemotherapy paclitaxel thus describing a novel combination treatment for this disease. Taken together, these results contribute to our understanding of how the ubiquitin-proteasome system positively and negatively regulates the abundance and activity of FOXM1. The research presented here further extends our understanding of the network of interactions regulating normal cell cycle dynamics and provide mechanistic and novel therapeutic insights into the promotion and treatment of cancer.Doctor of Philosoph